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Clinicopathologic Reports, Case Reports, and Small Case Series
March 2002

Cryotherapy as a Primary Treatment for Choroidal Melanoma

Arch Ophthalmol. 2002;120(3):400-403. doi:

The treatment of small melanocytic tumors of the uvea is appealing because of the prospect of local destruction of a potentially lethal tumor while it is still confined to the eye. However, enthusiasm for treating small melanocytic tumors of the uvea has been tempered by the lack of an effective local treatment that is free from significant local side effects and by the difficulty in identifying which small uveal melanocytic lesions should be treated. In the past few years, several studies have helped identify which small uveal melanocytic tumors are at particularly high risk for growth and/or metastasis.1,2 Identification of high-risk small tumors has prompted reevaluation of the management of these tumors and promoted the development of vision-sparing treatment modalities.

Cryotherapy has been used in a limited fashion for the treatment of uveal melanomas.3,4 Lincoff et al3 and Brovkina et al4 evaluated cryotherapy in small series of patients with uveal melanoma. In both series the effectiveness of cryotherapy was limited by exudative retinal detachment and incomplete tumor destruction. However, in both of these trials, medium to large melanomas were treated, and the treatment was designed to destroy the tumor in 1 treatment session. Herein we report a prospective trial of cryotherapy in the treatment of 5 patients with small, growing choroidal melanocytic tumors with the use of multiple treatment sessions to limit the complications of the procedure and to ultimately achieve a flat chorioretinal scar.

Patients, Materials, and Methods

Patients were considered eligible for this trial if (1) they had photographically documented growth of a choroidal lesion with the ophthalmoscopic and echographic features of a choroidal melanoma (photographically documented growth was defined as an increase in the size of the tumor, relative to retinal landmarks, as determined by comparison of serial color photographs); (2) the thickness of the choroidal tumor measured less than 3.0 mm; and (3) the basal diameter was less than 16 mm. Tumors that extended into the ciliary body were not included in this trial, but peripapillary tumors were eligible. This decision was based on the lack of vision-sparing options for patients with peripapillary choroidal melanomas. No specific minimum diameter or thickness was required as long as the tumor met the above requirement for documented growth. Patients were not included in the trial if they had undergone prior treatment for choroidal melanoma, including irradiation, laser, or surgery. All patients underwent pretreatment and posttreatment examination, color fundus photography, and A- and B-scan echography. Patients were examined at a minimum of 1 day prior to treatment, at the time of treatment, 1 day posttreatment, 7 to 14 days posttreatment, 3 months posttreatment, and then at 6-month intervals. Other visits were permitted at the discretion of the treating ophthalmologist. Visual acuities were recorded using a projected visual acuity system but were not standardized.

The tumors were treated with a double freeze-thaw method that uses a conventional retinal cryoprobe. The end point of each freeze was whitening of the surface of the tumor. Applications with the cryoprobe were placed in an overlapping fashion so that the entire tumor was treated. One patient (patient 3) with a peripapillary tumor was treated with an endocryoprobe to try to limit the damage to the optic nerve. Patients were re-treated at 4- to 6-week intervals until a flat chorioretinal lesion, as determined by ophthalmoscopy and echography, was present. The protocol was approved by the Oregon Health Sciences University Institutional Review Board for enrollment of 8 patients. Five patients were enrolled in the trial between 1989 and 1999, at which point recruitment was closed.

Results

The pretreatment and postreatment clinical features of the tumors are summarized in Table 1. Pretreatment and postreatment fundus photographs are shown in Figure 1. Treatment of all the tumors resulted in the desired clinical end point of a flat chorioretinal scar. This appearance was maintained throughout the follow-up period. The number of treatments required to achieve this end point varied from 2 to 5. In patients 4 and 5 there is a small central area of increased pigmentation (Figure 1 H-J), but these areas are completely flat and have not shown an increase in size over the follow-up period.

Clinical Characteristics
Clinical Characteristics
figure
Color fundus photographs of patients 1 (A and B), 2 (C and D), 3
(E and F), 4 (G and H), and 5 (I and J) before and after cryotherapy, respectively.

Color fundus photographs of patients 1 (A and B), 2 (C and D), 3 (E and F), 4 (G and H), and 5 (I and J) before and after cryotherapy, respectively.

Notable complications of the treatment included a visual acuity of no light perception in 1 patient (patient 1). This patient had a peripapillary tumor, and optic nerve damage resulted from direct cryo-injury to the optic nerve at the time of treatment. Loss of vision occurred immediately following cryotherapy and there was no recovery of vision following the injury. Patient 2 has age-related macular degeneration and developed a subfoveal neovascular membrane that is thought to be unrelated to the cryotherapy. Patient 3 developed a branch retinal vein occlusion that did not significantly affect her vision. Patient 5 developed a transient exudative retinal detachment and an epiretinal membrane with a reduction in visual acuity from 20/20 to 20/30.

Patient 1 died from renal and cardiovascular disease 125 months after treatment of his intraocular tumor. There was no clinical evidence of metastatic disease. An autopsy was not performed. Patients 2 through 5 are alive without clinical evidence of metastatic disease. The mean follow-up in the 5 patients is 65 months, with a range of 16 to 125 months.

Comment

Treatment of small, growing melanocytic tumors remains a controversial topic. Risk factors for growth of small melanocytic tumors have been reported in 2 studies. Shields et al1 found that greater initial tumor thickness, posterior margin of the tumor touching the optic nerve, symptoms of flashes and floaters, orange pigment on the surface of the tumor, and subretinal fluid predicted growth. The Collaborative Ocular Melanoma Study group found that factors predictive of the growth of small melanomas were a greater initial diameter or thickness, presence of orange pigment on the surface of the tumor, the absence of drusen, and the absence of retinal pigment epithelium changes at the margin of the tumor.2 Risk factors for metastasis of small choroidal melanomas have been reported as posterior margin of the tumor touching the optic nervehead, documented growth, and greater initial tumor thickness.1 Only small, growing melanomas were treated in this trial.

Cryotherapy has received little attention as a means of destroying uveal melanomas. Theoretically, this method has several potential advantages: (1) melanin-containing cells are sensitive to destruction by freezing; (2) cryotherapy is an accepted method of treating melanomas elsewhere, including the conjunctiva; (3) cryotherapy has been used for more than 20 years in treating retinal diseases, including vascular tumors, retinoblastoma, retinal tears, and retinal detachment; (4) when using cryotherapy, the approach is from the choroid; thus, in addition to a direct effect on the tumor cells, cryotherapy can have an additional effect of compromising the tumor's blood supply; and (5) transscleral treatment also results in treatment of intrascleral tumor cells.

The acute effects of cryotherapy on uveal melanomas has been studied by Hidayat et al.5 These authors found that following rapid freezing there were ultrastructural changes that included plasmalemmal breaks, dissolution of cytoplasmic matrix, and damage to cellular organelles all of which suggest a lethal effect on melanoma cells. These authors also studied one melanoma that was treated with rapid freezing 6 months prior to enucleation. The tumor was incompletely treated, but in the area of cryotherapy, there was extensive necrosis of tumor cells and infiltration with melanophages.

A substantial number of complications occurred in our small patient population. External cryotherapy to a peripapillary tumor resulted in a visual acuity of no light perception due to cryoinjury to the optic nerve. This complication was later avoided by using an endocryoprobe to successfully treat a second peripapillary tumor. Less severe complications included branch retinal vein occlusion, transient exudative retinal detachment, and epiretinal membrane formation. Despite these complications, 4 of the 5 patients maintained good visual acuity after cryodestruction of the tumor (1 subsequently lost vision in the treated eye owing to age-related macular degeneration).

Other options for treating small, growing melanomas include radiation therapy or transpupillary thermotherapy (TTT). Radiation therapy of small tumors carries with it a high likelihood of loss of central vision if the optic nerve or fovea receives a radiation dosage in excess of 3000 to 4000 rads equivalents.

What role cryotherapy and TTT will have in the treatment of small choroidal melanomas is not known. Both treatments require multiple treatment sessions to limit complications. Transpupillary thermotherapy has the advantage of not requiring conjunctival incisions and having a more discrete border between treated and untreated areas. Cryotherapy has the advantage of a visual end point to each treatment session. Unlike TTT, cryotherapy is a transscleral treatment and should result in treatment of the intrascleral tumor in the area of cryotherapy. Certain tumor characteristics may be a relative indication for one type of treatment, eg, tumor pigmentation and location. More peripheral tumors may be easier to treat with cryotherapy while posterior tumors may be easier to treat with TTT. Transpupillary thermotherapy appears at this time to be more effective in more pigmented tumors, so lack of pigmentation may be a relative indication for cryotherapy. Finally, the 2 treatments are not mutually exclusive and may find utility in combination with each other, or with irradiation. Both treatments could find utility in the treatment of marginal recurrences of initially irradiated tumors. Whether either TTT or cryotherapy will result in permanent tumor eradication requires further follow-up of treated patients. The mean follow-up in this trial was 65 months, but given the small size of the tumors and the slow growth of uveal melanomas, additional time is necessary to be certain late recurrences will not develop.

In conclusion, we have used cryotherapy to treat 5 patients with small, growing melanocytic tumors. All tumors were treated to an end point of a flat chorioretinal scar and maintained this end point over the follow-up period. Using multiple treatment sessions, we were able to avoid the incomplete tumor destruction and intraocular morbidity reported in earlier trials about the cryodestruction of choroidal melanomas.

This study was supported in part by an unrestricted grant from Research to Prevent Blindness, New York, NY.

Corresponding author: David J. Wilson, MD, Casey Eye Institute, Oregon Health Sciences University, 3375 SW Terwilliger Blvd, Portland, OR 97201 (e-mail: wilsonda@ohsu.edu).

References
1.
Shields  CLShields  JAKiratli  HDe Potter  PCater  JR Risk factors for growth and metastasis of small choroidal melanocytic lesions. Ophthalmology. 1995;1021351- 1361Article
2.
Collaborative Ocular Melanoma Study Group, Factors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. Arch Ophthalmol. 1997;1151537- 1544Article
3.
Lincoff  HMcLean  JLong  R The cryosurgical treatment of intraocular tumors. Am J Ophthalmol. 1967;63389- 399
4.
Brovkina  AFZiangirova  GGKornarov  BA Cryodestruction of choroidal melanomas. Vestn Oftalmol. 1977;261- 63
5.
Hidayat  AALaPiana  FGKramer  KKWhitmore  PVWertz  FDRao  NA The effect of rapid freezing on uveal melanomas. Am J Ophthalmol. 1987;10366- 80
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